The former midfielders regularly locked horns during their playing careers and meet again when their sides do battle in the last 16 of Europe's premier club competition.
Both coaches played for their current clubs and to add spice to the tie, they also turned out for the city rivals of their opponents on Wednesday.
Seedorf has fond memories of the Champions League, as he was the first player to win the competition three times with different clubs and has four winners' medals in his collection.
Simeone never lifted the famous trophy in his playing days, but won the UEFA Cup during his time at Inter and the Europe League in his tenure at Atletico in 2012.
The Liga title contenders arrive in Italy as one of only three sides to avoid defeat in the group stages, winning five of their six games en route to the last 16.
Atletico face a Milan side blighted by inconsistency this season and they have struggled against Spanish opposition at San Siro.
In eight matches against La Liga sides Milan have only won once, a 2-0 victory at this stage of last season's competition against Barcelona, and have lost their last four knockout ties against Spanish opponents.
Atletico have won three times in their eight visits to Italy as they prepare to face Milan for the first time in European competition.
Both sides have strikers in form and the outcome of the first-leg tie could hinge on the service provided for Mario Balotelli and Diego Costa.
Costa has 26 goals to his name in all competitions this season, with four in his last three in Europe, but Balotelli has scored five in his last six appearances - including a stunning late winner against Bologna last Friday.
Seedorf will be without midfield duo Riccardo Montolivo and Sulley Muntari through suspension, while there are also doubts over Kaka (ankle) and Cristian Zapata (thigh).
The visitors will be without Tiago (wrist), Filipe Luis (groin) and Javi Manquillo (back).
